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Altered amyloid-ß structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion.
Pagnon de la Vega, María; Syvänen, Stina; Giedraitis, Vilmantas; Hooley, Monique; Konstantinidis, Evangelos; Meier, Silvio R; Rokka, Johanna; Eriksson, Jonas; Aguilar, Ximena; Spires-Jones, Tara L; Lannfelt, Lars; Nilsson, Lars N G; Erlandsson, Anna; Hultqvist, Greta; Ingelsson, Martin; Sehlin, Dag.
Afiliación
  • Pagnon de la Vega M; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Syvänen S; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Giedraitis V; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Hooley M; UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
  • Konstantinidis E; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
  • Meier SR; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Rokka J; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Eriksson J; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Aguilar X; Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden.
  • Spires-Jones TL; PET Centre, Uppsala University Hospital, Uppsala, Sweden.
  • Lannfelt L; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Nilsson LNG; UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
  • Erlandsson A; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
  • Hultqvist G; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
  • Ingelsson M; BioArctic AB, Stockholm, Sweden.
  • Sehlin D; Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway.
Acta Neuropathol Commun ; 12(1): 22, 2024 Feb 05.
Article en En | MEDLINE | ID: mdl-38317196
ABSTRACT
Deposition of amyloid beta (Aß) into plaques is a major hallmark of Alzheimer's disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aß. We recently identified the Uppsala APP mutation (APPUpp), which causes Aß pathology by a triple mechanism increased ß-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aß conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aß pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aß pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased ß-secretase cleavage and suppressed α-secretase cleavage, resulting in AßUpp42 dominated diffuse plaque pathology appearing from the age of 5-6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aß pathology in all models, whereas the Aß protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aß pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AßUpp42 aggregates were found to affect their interaction with anti-Aß antibodies and profoundly modify the Aß-mediated glial response, which may be important aspects to consider for further development of AD therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos beta-Amiloides / Enfermedad de Alzheimer Límite: Animals / Humans Idioma: En Revista: Acta Neuropathol Commun Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos beta-Amiloides / Enfermedad de Alzheimer Límite: Animals / Humans Idioma: En Revista: Acta Neuropathol Commun Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido